Several patents are referenced in this application in order to more fully describe the state of the art to which this invention pertains. The disclosure of each of these patents is incorporated by reference herein.
Criteria related to drug mechanism of action, concentration, onset and duration of activity, target tissue selectivity and in vivo stability are important factors in selecting a specific method for drug delivery.
There are six principal routes for drug delivery. Oral delivery is the most common and utilizes unit doses in the form of tablets, capsules, syrups and the like for ingestion and ultimate transport across the gastrointestinal mucosa into systemic distribution. Troches are employed for buccal absorption in the oral cavity and to a lesser extent sublingual application. Atomization for inhalation and absorption by nasal or bronchial membranes has found substantial application for rapid absorption of selected medications. Topical or transdermal adsorption is a preferred method for extended release drug delivery amounting to many hours or several days. Rectal administration by means of suppositories is a further method for drug absorption. Finally, intramuscular injection and intravenous delivery, while invasive techniques, may be the only available options for the medication of interest.
Of the commonly employed drug delivery methods, sublingual delivery probably has the fewest applications of all contemporary methods despite a significant number of advantages. Firstly, the sublingual cavity is highly vascularized. Specifically, the sublingual cavity contains arterial and venous networks embedded in the base of the anterior oral cavity under the tongue in addition to the lingual artery and venae comitante embedded in the underside of the tongue. This vascularization complex communicates directly with the internal jugular vein. Therefore drug absorption in this region bypasses the liver on the first circulation. The advantage of this bypass is that the liver is the principal drug dissipating organ and is largely responsible for the depletion of systemically circulating drugs. Secondly, the sublingual cavity is a catabolically benign region with few, if any, drug degrading chemistries operating within the protected cavity. This is in stark contrast to orally ingested medications which are subjected to degradative environments associated with the gastrointestinal tract. Thirdly, in contrast to the buccal region there is only a thin epithelial barrier to drug transport across the mucosal lining. Finally, the sublingual cavity contains no known flavor sensory organelles which is important as many drugs exhibit a bitter characteristic on exposure to the dorsal papilla of the tongue.
In spite of its theoretical appeal, however, the sublingual route of administration has not found widespread use as the method of choice for drug delivery. The best known application is administration of nitroglycerin in a rapidly disintegrating dosage for treatment of angina pectoris. Nitroglycerin is rapidly transported across the sublingual mucosa giving immediate relief via ultimate communication with the internal jugular vein.
There are probably several factors operating collectively to create a bias against sublingual administration of drugs. Firstly, the sublingual cavity is readily stimulated to activate the sublingual gland to produce saliva in order to rinse the cavity. This can result in dilution and transport of the drug into the back of the oral cavity ultimately entering the esophageal tract and the stomach. Secondly, there are attendant taste consequences of release from the sublingual cavity and dissemination of the drug of interest into other areas of the oral cavity. Finally, sublingual administration of drugs delivered in tablet or capsule form is uncomfortable relative to ingestion.
Pharmaceutical agents to be delivered as an individual dose in tablet and capsule form are easy to manufacture. They are commonly packaged as a loose count in vials, jars, or bottles. Alternatively, they may be dispensed from thermoformed blister packs, which are continuously produced from a roll stock, packaging film matrix. The film is heated to its thermoplastic temperature and subjected to an automated die molding process to produce an array of indented wells or depressions projecting from the plane of the film. After indentation of the film, preformed dose forms such as tablets and capsules are flooded across the indented film surface to saturate the well sites. The excess tablets or capsules are removed from the flooded area and the loaded blister array is lidded by the application of a heat sealable web closure. The line or array of unit packaged dose forms is typically segmented into a cluster of contiguous units for final packaging thereby forming a blister pack. The blister pack can be subsequently perforated along a tear line to allow for easy removal of individual, unopened doses from the main body of the blister pack cluster.
A variation of this conventional thermoform, fill and seal process for preformed pharmaceutical dosage units is the use of the technique to produce dosage units that are formed in situ by lyophilization. See, for example, U.S. Pat. Nos. 4,305,502 and 5,729,958.
There are several advantages to unitized compartmentalization of a preformed, individual dose form versus multi-unit bulk packaging. Firstly, the environment of the contained dose form can be controlled. Many drugs in conventional dose form are susceptible to oxidation, photolysis, or hydrolysis. Appropriate design or selection of the encapsulating package matrix can relieve these problems. Secondly, unit containment offers the convenience of carrying one or two individual doses unobtrusively without the possibility of microbial, chemical, or physical contamination.
Dosage units in thin form, such as films or troches, on the other hand, are difficult to manufacture, particularly those with an unusual shape. Additionally, the indexing and packaging is more complex. Continuous cast films containing active substances derived from water soluble or dispersible matrices typically require the added complication of casting onto a sacrificial support film to achieve sufficient strength for collection and converting. As an example, a viscous polymeric fluid containing the drug of interest is extruded onto a continuous advancing belt which moves into a thermally elevated environment. Typically the belt is heated by conduction from the bottom with steam and the exposed surface of the film is subjected to a heated, forced air stream. The dried continuous cast film, with or without backing film, is removed from the belt and collected as roll stock. The roll stock is delaminated if a support film was employed and converted by standard die cutting methods or other segmentation processing into individual dosage forms. The dosage forms are then indexed and packaged into a loose fill dispenser. Film-like dosage forms produced by this approach, in contrast to tablets or capsules, are extremely difficult to count, index, and transfer into a convenient multidose package form that allows for the delivery of a single dose without compromise of the packaging integrity of the remaining units. A dosage unit that could be economically produced in the form of a thin film or troche with individualized packaging for each dose would alleviate these difficulties.